Transcriptomic analysis of naturally occurring bovine respiratory disease in Australian feedlot cattle identifies bovine viral diarrhoea virus-induced immunosuppression and Mollicutes as the dominant drivers of lung inflammation.

Bovine respiratory disease (BRD) is the most economically significant syndrome of feedlot cattle worldwide, yet the relative contributions of individual BRD pathogens to host transcriptional responses remain poorly understood. We performed pathogen-stratified transcriptomic analysis of lung tissue obtained from naturally occurring BRD cases (n = 22) and non-BRD controls (n = 9) in feedlot cattle. BRD-affected tissue showed significant immune activation with 3148 differentially expressed genes (DEGs; 18.7% of the 16,873 genes tested), of which 70.4% were upregulated. Pathogen-stratified analysis revealed significant heterogeneity in host response (221-2241 DEGs per pathogen). Bovine viral diarrhoea virus (BVDV) was associated with a distinct immunomodulatory signature (79% of genes downregulated), consistent with its immunosuppressive role. Mollicutes showed the strongest transcriptional overlap with the core BRD signature: Mycoplasmopsis arginini, Metamycoplasma alkalescens and Metamycoplasma canadense shared 53-71% of their differentially expressed genes with the core BRD signature with 100% directional concordance, whereas Mycoplasmopsis bovis showed lower overlap (34%) despite near-ubiquitous detection (87.1%). Mycoplasmopsis arginini induced the largest transcriptional footprint (2241 DEGs), with 1316 genes (58.7%) overlapping the core BRD signature, representing 41.8% of all BRD DEGs, suggesting it may have an important role in BRD pathogenesis. Pasteurella multocida and Histophilus somni ranked among the top three in the integrated analysis, accounting for 77% of dose-responsive gene associations with load-dependent inflammatory amplification. It is hypothesised that in naturally occurring BRD in feedlots, BVDV was associated with suppressed host immunity; Mollicutes were associated with the core inflammatory transcriptome; and Gram-negative bacteria were associated with amplified host response proportionally to the bacterial load. These findings provide an important rationale for future diagnosis, treatment, prevention and control of BRD in Australian feedlots.